Pancreatic beta cell failure leads to insulin deficiency and diabetes. Beta cell ER stress, which occurs due to cellular insults like peptide misfolding, immune attack, lipotoxicity or oxidative stress, is a well-documented cause of insulin production failure and beta cell death. Protecting beta cells from ER stress or tipping the balance away from the ER stress death response can maintain metabolic health and prevent diabetes. An important goal is therefore to improve understanding of the beta cell ER stress tipping point, in order to find ways to keep beta cells in the functional range and avoid losing them to decompensated stress. Grp78, the focus of this project, is a central regulator of ER health. During normal unstressed cell function, Grp78 acts as a chaperone and also associates with, and inhibits, the three ER transmembrane unfolded protein response (UPR) activators. Grp78 is a critical sensor of ER stress level and regulator of the cell response to stress. When ER stress increases, Grp78 is titrated away by unfolded peptide, de-repressing the UPR activators, allowing downstream signaling to expand ER capacity to accommodate the increased workload and relieve stress. Grp78 is itself a transcriptional target of UPR; adaptation to stress results in increased Grp78 abundance. Thus, Grp78 is the centerpiece of a carefully balanced mechanism to maintain the secretory peptide synthesis apparatus. The goal of this project is to describe the biology of Grp78 in beta cells, so as to learn more about the critical tipping-point between tolerable stress and decompensation. Preliminary data shows that Grp78 is absolutely required for beta cell homeostasis. Mice lacking Grp78 develop diabetes in the first few weeks of life; insulin production failure is caused by accelerated beta cell death, associated with an unexplained loss of beta cell differentiation status. For this project we have assembled a team including Amy Lee, the scientist who cloned Grp78 in the 1980s and generated many related tools including the Grp78-floxed mice, and Jason Kim, a metabolism expert with the tools to perform state-of-the-art in vivo quantification of insulin secretion. In three focused aims we will carefully assess the metabolic and molecular impact of beta cell deletion of one or both alleles of Grp78 during beta cell fetal development, postnatal maturation and adulthood, under basal and insulin-demand stressed conditions. We will examine the tipping-point between adaptive UPR and decompensation in both mice and human islets, with a detailed exploration of how cell death is triggered, and the novel and exciting relationship between Grp78 and beta cell maturation and identity maintenance. When completed, these studies will clarify the molecular stress pathways that determine whether beta cells successfully adapt or succumb to decompensation during Grp78 reduction.